A protease is an enzyme that degrades proteins into smaller peptide fragments. Cysteine proteases incorporate a cysteine residue that is essential to the catalytic process.
Calpains are cysteine proteases that are activated by elevated levels of intracellular calcium ions. Under normal circumstances, calcium ion signalling of calpain leads to controlled proteolysis during cytoskeletal remodelling, signal transduction and apoptosis in mammals. Uncontrolled or high levels of calcium ions in a cell can cause excessive calpain activity, and lead to tissue damage.
There are two major isoforms of calpain, which require different concentrations of calcium ions for activity. They are μ-calpain (also known as calpain I or calpain 1) and m-calpain (also known as calpain II or calpain 2). The μ-calpain isoform has been identified as the major isoform present during pathological conditions of the nervous system such as Alzheimer's disease, motor neuron damage, muscular dystrophy and stroke.
The m-calpain isoform has been associated with the development of cataracts. Cataracts are a condition whereby the lens of an eye becomes increasingly clouded and eventually results in blindness. The clouding is due to the precipitation of degraded lens proteins that results from sustained activity of the calcium ion-activated calpain.
Several classes of calpain inhibitors are known. However, many of the known calpain inhibitors have limited therapeutic potential because they have poor stability, cell permeability, solubility or selectivity, or because they have high cell toxicity.
Accordingly, it is an object of the present invention to go some way to avoiding the above disadvantages or to at least provide the public with a useful choice.
Other objects of the invention may become apparent from the following description which is given by way of example only.
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date.